Discovery of a Lead Compound for Specific Inhibition of Type I Collagen Production in Fibrosis

Increased Ito cell collagen production occurs during in vivo liver fibrogenesis. Regulation of the overproduction of collagen was studied in cultured rat hepatic Ito cells, which resemble the myofibroblast associated with liver fibrosis. Previous studies suggest that the steroid hormones, retinoic acid, and glucocorticoids may have antifibrogenic properties in vitro and in vivo when used at pharmacological doses. Their potential roles at physiological levels are not well understood. The current study examined the potential regulation of the overproduction of type I collagen in cultured rat hepatic Ito cells by another steroid hormone, 3,5,3'-triiodo-L-thyronine (T3). T3 induced a 3.4-fold reduction in type I collagen production. The effect was dose dependent and was maximal with physiological levels of T3 (10(-9) M). The effect of T3 was independent of any suppression in total protein synthesis. The mechanism of the suppressive effect of T3 on collagen production was explored and was found to be at a posttranslational level. This study suggests that the inhibitory effects of T3 on type I collagen production are likely caused by enhanced intracellular turnover of type I collagen.

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Influence of IgE-mediated activation of cultured human mast cells on proliferation and type I collagen production by human dermal fibroblasts

Journal of Allergy and Clinical Immunology ◽

10.1067/mai.2000.106059 ◽

2000 ◽

Vol 106 (1) ◽

pp. S72-S77 ◽

Cited By ~ 12

Author(s):

Masatoshi Abe ◽

Motohiro Kurosawa ◽

Yasushi Igarashi ◽

Osamu Ishikawa ◽

Yoshiki Miyachi

Keyword(s):

Mast Cells ◽

Type I Collagen ◽

Dermal Fibroblasts ◽

Type I ◽

Human Dermal Fibroblasts ◽

Collagen Production ◽

Human Mast Cells ◽

Ige Mediated

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Modulation by 17,20S(OH)2pD of Fibrosis-Related Mediators in Dermal Fibroblast Lines from Healthy Donors and from Patients with Systemic Sclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms23010367 ◽

2021 ◽

Vol 23 (1) ◽

pp. 367

Author(s):

Monica L. Brown Lobbins ◽

Andrzej T. Slominski ◽

Karen A. Hasty ◽

Sicheng Zhang ◽

Duane D. Miller ◽

...

Keyword(s):

Systemic Sclerosis ◽

Type I Collagen ◽

Dermal Fibroblast ◽

Positive Control ◽

Dermal Fibroblasts ◽

Normal Donor ◽

Type I ◽

Collagen Production ◽

Healthy Donors ◽

Tgf Β1

We previously demonstrated that the non-calcemic pregnacalciferol (pD) analog 17,20S (OH)2pD suppressed TGF-β1-induced type I collagen production in cultured normal human dermal fibroblasts. In the present studies, we examined fibroblasts cultured from the lesional skin of patients with systemic sclerosis (scleroderma (SSc)) and assessed the effects of 17,20S(OH)2pD on fibrosis-related mediators. Dermal fibroblast lines were established from skin biopsies from patients with SSc and healthy controls. Fibroblasts were cultured with either 17,20S(OH)2pD or 1,25(OH)2D3 (positive control) with/without TGF-β1 stimulation and extracted for protein and/or mRNA for collagen synthesis and mediators of fibrosis (MMP-1, TIMP-1, PAI-1, BMP-7, PGES, GLI1, and GLI2). 1 7,20S(OH)2pD (similar to 1,25(OH)2D3) significantly suppressed net total collagen production in TGF-β1-stimulated normal donor fibroblast cultures and in cultures of SSc dermal fibroblasts. 17,20S(OH)2pD (similar to 1,25(OH)2D3) also increased MMP-1, BMP-7, and PGES and decreased TIMP-1 and PAI1 expression in SSc fibroblasts. Although 17,20S(OH)2pD had no effect on Gli1 or Gli2 in SSc fibroblasts, it increased Gli2 expression when cultured with TGF-β1 in normal fibroblasts. These studies demonstrated that 17,20S(OH)2pD modulates mediators of fibrosis to favor the reduction of fibrosis and may offer new noncalcemic secosteroidal therapeutic approaches for treating SSc and fibrosis.

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